Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
  • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
  • C07D295/182—Radicals derived from carboxylic acids
  • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
  • C07C233/04—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
  • C07C233/07—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
  • C07D339/02—Five-membered rings
  • C07D339/04—Five-membered rings having the hetero atoms in positions 1 and 2, e.g. lipoic acid
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention relates to new therapeutically useful 1,2-dithiol-3-ylideneammonium derivatives, to processes for their preparation and pharmaceutical compositions containing them.
• the 1,2-dithiol-3-ylideneammonium derivatives of the present invention are those compounds of the general formula: ##STR2## wherein X.sup. ⁇ represents an anion, R represents a straight- or branched-chain alkyl radical containing 1 to 7 carbon atoms [unsubstituted or substituted by a hydroxy, carboxy, alkoxycarbonyl, cyano, dialkylamino or alkylcarbonyl radical or a benzoyl radical the phenyl ring of which is unsubstituted or substituted by one or more halogen atoms or radicals selected from alkyl (optionally substituted by one or more halogen atoms), alkoxy, hydroxy, amino, alkylamino, dialkylamino, cyano and nitro, or a thenoyl radical the thienyl ring of which is unsubstituted or substituted by one or more halogen atoms or radicals selected from alkyl,
• R 1 represents a phenyl radical unsubstituted or substituted by one or more halogen atoms or radicals selected from alkyl (optionally substituted by one or more halogen atoms), alkoxy, hydroxy, amino, alkylamino, dialkylamino, cyano and nitro, or alternatively represents a cycloalkyl radical containing 3 to 7 carbon atoms, or an alkyl or phenylalkyl radical, and R 2 represents a hydrogen atom, and also the corresponding bases (viz. no anion X.sup. ⁇ is present) when R 2 represents hydrogen.
• the alkyl and alkoxy radicals and moieties which have been heretofore mentioned or are mentioned hereafter contain 1 to 4 carbon atoms in a straight- or branched-chain.
• the compounds of general formula (I) are prepared by reacting a compound of the general formula:
• R is as hereinbefore defined and X 1 represents a halogen atom such as chlorine, bromine or iodine, or another reactive ester radical such as a mesyloxy or tosyloxy radical
• X 1 represents a halogen atom such as chlorine, bromine or iodine, or another reactive ester radical such as a mesyloxy or tosyloxy radical
• R 1 and R 2 are as hereinbefore defined, and then isolating the product of general formaula (I) obtained and, optionally, converting it to another salt or to the corresponding base when R 2 represents a hydrogen atom.
• the reaction can be carried out in an inert organic solvent at a temperature between 40° C. and the reflux temperature of the reaction mixture.
• the salt isolated in this case is generally the iodide.
• an acid addition salt of the reactant of general formula (II) may be used.
• the 1,2-dithiol-3-thiones of general formula (III) can be prepared by cycling a propionic acid ester of the general formula: ##STR4## wherein R 1 and R 2 are as hereinbefore defined and R' represents an alkyl radical, by means of a thionating reagent, such as P 4 S 10 or PEDERSEN-LAWESSON's reagent [i.e. 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3-dithia-2,4-diphosphetane].
• a thionating reagent such as P 4 S 10 or PEDERSEN-LAWESSON's reagent [i.e. 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3-dithia-2,4-diphosphetane].
• the reaction is carried out under conditions analogous to those described by B. S. PEDERSEN and S. O.
• the propionic acid esters of general formula (IV) can be prepared by reacting an amine of the general formula: ##STR5## (wherein R 1 and R 2 are as hereinbefore defined) with an alkyl chloroformylacetate, or in accordance with the method of F. D. CHATTAWAY et al., J. Chem. Soc. 97, 939 (1910).
• the new compounds of general formula (I) wherein R 2 represents a hydrogen atom obtained by the aforedescribed process can be converted to the corresponding bases by reaction with an alkali metal bicarbonate, sodium hydroxide or potassium hydroxide, in an aqueous medium. If the base precipitates in the medium, it is isolated by filtration; otherwise, it is extracted with the aid of an organic solvent.
• the base can be obtained directly, without isolating the intermediate salt, by carrying out the condensation of the compounds of general formulae (II) and (III) in the presence of a proton acceptor, such as triethylamine.
• the bases thus derived from compounds of general formula (I) can be converted to acid addition salts by the addition of acids, in suitable solvents.
• suitable solvents are alcohols, ketones, ethers or chlorinated hydrocarbons.
• the acid addition salt formed precipitates, if necessary after concentration or its solution; the salt is separated by filtration or decantation.
• the new compounds of general formula (I) wherein R 1 represents a phenyl, cycloalkyl, alkyl or phenylalkyl radical and R 2 represents a cycloalkyl, alkyl or phenylalkyl radical are also prepared by reacting a compound of the general formula:
• R' 2 represents a cycloalkyl, alkyl or phenylalkyl radical and X 2 represents a haloen atom or another reactive ester radical, such as mesyloxy or tosyloxy radical, with a product of general formula (I) wherein R 1 represents a phenyl, cycloalkyl, alkyl or phenylalkyl radicals and R 2 represents a hydrogen atom.
• the reaction can be carried out in an inert organic solvent normally used when quaternising an amine.
• the products of the general formula (I) can be converted to another salt by any trans-salification method known per se and which is compatible with the nature of the initial anion.
• the compounds of general formula (I) can be purified by the usual methods, in particular by crystallisation or chromatography.
• 1,3-Dithiol-3-ylideneamine derivatives are known from the publication of F. BOBERG et al., J. Prakt. Chem. 315, 970 (1973), from the publication of G. CAILLAUD and Y. MOLLIER, Bull. Soc. Chim. France 72, 147 (1972), and from French Pat. No. 2011918.
• the products described in the said patent are presented as agricultural antifungal agents. None of the three publications mentioned above indicates pharmacological properties for the products described.
• R represents an alkyl radical containing 2 to 4 carbon atoms, or a straight- or branched-chain alkyl radical containing 1 to 7 carbon atoms [unsubstituted or substituted by a cyano, dialkylamino, carbamoyl, alkylcarbonyl or thenoyl radical, or a benzoyl radical the phenyl ring of which is unsubstituted or substituted by one or more halogen atoms or radicals selected from alkyl, alkoxy, hydroxy and cyano] and R 1 and R 2 together with the nitrogen atom to which they are attached represent a pyrrolidin-1-yl or morpholino radical.
• R represents a methyl or ethyl radical unsubstituted or substituted by a benzoyl radical the phenyl ring of which is unsubstituted or substituted by one or more halogen atoms or radicals selected from alkyl, alkoxy, hydroxy and cyano, and R 1 and R 2 together with the nitrogen atom to which they are attached represent the morpholino radical.
• anions which can lead to pharmaceutically acceptable salts there may be mentioned inorganic anions (such as chlorides, bromides, iodides, sulphates, nitrates and phosphates) or organic anions (such as acetates, propionates, succinates, benzoates, fumarates, maleates, theophylline-acetates, salicylates, phenolphthalinates and methylene-bis- ⁇ -hydroxynaphthoates).
• inorganic anions such as chlorides, bromides, iodides, sulphates, nitrates and phosphates
• organic anions such as acetates, propionates, succinates, benzoates, fumarates, maleates, theophylline-acetates, salicylates, phenolphthalinates and methylene-bis- ⁇ -hydroxynaphthoates.
• Methyl iodide (21.3 g) is added to a suspension of 5-dimethylamino-1,2-dithiol-3-thione (17.7 g) in acetone (350 cc) and the mixture is heated under reflux for 1 hour. After cooling, the insoluble product formed is filtered off and washed with acetone (2 ⁇ 20 cc). After two successive recrystallisations of the crude product from water, N-(5-methylthio-1,2-dithiol-3-ylidene)-dimethylammonium iodide (14.2 g), melting at 226° C., is obtained.
• 5-Dimethylamino-1,2-dithiol-3-thione can be prepared by reacting ethyl 3-dimethylamino-3-oxopropionate (51 g) with phosphorus pentasulphide (107.5 g) in pyridine (640 cc) under reflux for 1 hour. After cooling to a temperature of about 20° C., the reaction mixture is poured into water (6.4 liters) and the insoluble product is extracted with methylene chloride (1 liter). The aqueous phase is then separated by decantation and washed with methylene chloride (2 ⁇ 500 cc).
• the methylene chloride phases are combined, dried over sodium sulphate and then concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C.
• the residue is dissolved in methylene chloride (1 liter) and the solution thus obtained is poured onto silica gel (1.1 kg) contained in a column of diameter 5.9 cm. Elution is carried out with methylene chloride (8 liters); this eluate is discarded. Elution is then carried out with methylene chloride (4 liters) and the corresponding eluate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C.
• Ethyl 3-dimethylamino-3-oxopropionate can be prepared in accordance with the method described by A. Ermili et al., J. Org. Chem. 30, 339 (1965).
• 5-Diethylamino-1,2-dithiol-3-thione can be prepared by reacting phosphorus pentasulphide (12.4 g) with ethyl 3-diethylamino-3-oxopropionate (7 g) in pyridine (92 cc) under reflux for 1 hour.
• the reaction mixtue is cooled to a temperature of about 20° C., treated with water (925 cc) and extracted with methylene chloride (successively 105 cc and 2 ⁇ 75 cc).
• Ethyl 3-diethylamino-3-oxopropionate can be prepared by reacting diethylamine (7.3 g) with ethyl chloroformylacetate (15 g), in the presence of triethylamine (10.1 g), in methylene chloride (100 cc) at a temperature of about 20° C. for 2 hours.
• 5-(N-Methylbutylamino)-1,2-dithiol-3-thione can be prepared by reacting phosphorous pentasulphide (114 g) with ethyl 3-(N-methylbutylamino)-3-oxopropionate (69.4 g) in pyridine (850 cc) under reflux for 1 hour. The reaction mixture is then cooled to a temperature of about 20° C. and then hydrolysed with distilled water (8.5 liters) and extracted with methylene chloride (980 cc and then 2 ⁇ 700 cc).
• Ethyl 3-(N-methylbutylamino)-3-oxopropionate can be prepared by reacting N-methylbutylamine (34.7 g) with ethyl chloroformylacetate (60 g), in the presence of triethylamine (40.3 g), in methylene chloride (400 cc) at a temperature of about 20° C. for 2 hours.
• 5-(N-Methylphenethylamino)-1,2-dithiol-3-thione can be prepared by reacting phosphorus pentasulphide (38.4 g) with ethyl 3-(N-methylphenethylamino)-3-oxopropionate (28.7 g) in pyridine (290 cc) under reflux for 1 hour. The reaction mixture is then cooled to a temperature of about 20° C. and hydrolysed with distilled water (3,500 cc) and extracted with methylene chloride (6 ⁇ 500 cc).
• Ethyl 3-(N-methylphenethylamino)-3-oxopropionate can be prepared by reacting N-methylphenethylamine (15.6 g) with ethyl chloroformylacetate (18.7 g) in the presence of triethylamine (12.6 g), in methylene chloride (125 cc) at a temperature of about 20° C. for 3 hours.
• 5-(N-Methylbenzylamino)-1,2-dithiol-3 -thione can be prepared by reacting phosphorus pentasulphide (93 g) with ethyl 3-(N-methylbenzylamino)-3-oxopropionate (66 g) in pyridine (650 cc) under reflux for 1 hour. After cooling to a temperature of about 20° C., the reaction mixture is hydrolysed with distilled water (6 liters) and extracted with methylene chloride (5 ⁇ 500 cc).
• Ethyl 3-(N-methylbenzylamino)-3-oxopropionate can be prepared by reacting N-methylbenzylamine (36.3 g) with ethyl chloroformylacetate (45.2 g), in the presence of triethylamine (30.3 g), in methylene chloride (300 cc) at 20° C. for 4 hours. After hydrolysis of the reaction mixture with distilled water (300 cc), the organic phase is washed with distilled water (300 cc) and then with a 1 N aqueous solution of hydrochloric acid (300 cc) and distilled water (2 ⁇ 300 cc).
• 5-(N-Methylphenylamino)-1,2-dithiol-3-thione can be prepared by reacting phosphorus pentasulphide (127 g) with ethyl 3-(N-methylphenylamino)-3-oxopropionate (85 g) in pyridine (950 cc) under reflux for 1 hour. After cooling to a temperature of about 20° C., the reaction mixture is hydrolysed with distilled water (7 liters) and extracted with methylene chloride (3 ⁇ 900 cc).
• Ethyl 3-(N-methylphenylamino)-3-oxopropionate can be prepared by reacting N-methylphenylamine (42.6 g) with ethyl chloroformylacetate (60 g), in the presence of triethylamine (40.3 g), in methylene chloride (400 cc) at a temperature of about 20° C. for 2 hours.
• the product can be distilled at 138°-142° C. under 0.5 mm Hg (0.067 kPa).
• a solution of methyl iodide (3.45 g) in acetone (11 cc) is added to a solution of 5-(N-methylcyclohexylamino)-1,2-dithiol-3-thione (4 g) in acetone (55 cc) under reflux, and reflux is maintained for 1 hour. After cooling to a temperature of about 20° C., the insoluble product formed is filtered off and then washed with acetone (3 ⁇ 20 cc) and diethyl ether (2 ⁇ 20 cc).
• 5-(N-Methylcyclohexylamino)-1,2-dithiol-3-thione can be prepared by reacting phosphorus pentasulphide (149 g) with ethyl 3-(N-methylcyclohexylamino)-3-oxopropionate (97 g) in pyridine (1110 cc) under reflux for 1 hour. After cooling to a temperature of about 20° C., the reaction mixture is hydrolysed with distilled water (6.5 liters) and then extracted with methylene chloride (1,300 cc and then 2 ⁇ 950 cc).
• Ethyl 3-(N-methylcyclohexylamino)-3-oxopropionate can be prepared by reacting N-methylcyclohexylamine (52.6 g) with ethyl chloroformylacetate (70 g), in the presence of triethylamine (47 g), in methylene chloride (470 cc) at a temperature of about 20° C. for 2 hours.
• Methyl iodide (10.65 g) is added to a suspension of 5-(pyrrolidin-1-yl)-1,2-dithiol-3-thione (10.51 g) in acetone (200 cc), and the reaction mixture is heated under reflux for 2 hours. After cooling to a temperature of about 20° C., the insoluble product is filtered off and washed with acetone (2 ⁇ 30 cc). After recrystallisation of the resulting product from water (200 cc), N-(5-methylthio-1,2-dithiol-3-ylidene)-pyrrolidinium iodide (14.8 g), melting at 197° C., is obtained.
• 5-(Pyrrolidin-1-yl)-1,2-dithiol-3-thione can be prepared by reacting phosphorus pentasulphide (287.5 g) with ethyl 3-(pyrrolidin-1-yl)-3-oxopropionate (160 g) in pyridine (1,600 cc) under reflux for 1 hour. After cooling to a temperature of about 20° C., the reaction mixture is hydrolysed with distilled water (11 liters) and extracted with methylene chloride (successively 1,600 cc and then 3 ⁇ 500 cc).
• Ethyl 3-(pyrrolidin-1-yl)-3-oxopropionate can be prepared by reacting pyrrolidine (94.4 g) with ethyl chloroformylacetate (200 g), in the presence of triethylamine (134.4 g), methylene chloride (1,340 cc) at a temperature of about 20° C. for 2 hours.
• the crude product obtained is recrystallised from a mixture of distilled water (215 cc) and ethanol (215 cc) and then stirred for 15 minutes in the presence of distilled water (200 cc) at a temperature of about 60° C. After filtration and drying, N-(5-phenacylthio-1,2-dithiol-3-ylidene)pyrrolidinium iodide (10.9 g), melting point at 179°-180° C., is obtained.
• Triethylamine (4.35 g) is added dropwise, in the course of 5 minutes, to a suspension of 2-diethylamino-1-chloroethane hydrochloride (7.4 g), 5-(pyrrolidin-1-yl)-1,2-dithiol-3-thione (4.45 g) and sodium iodide (9.9 g) in a mixture of acetone (110 cc) and dimethylformamide (25 cc) under reflux, and the reaction mixture is kept under reflux for 6 hours and then filtered at a temperature of about 50° C. in order to separate the insoluble product formed.
• a suspension of 5-(pyrrolidin-1-yl)-1,2-dithiol-3-thione (2 g), 4-chloromethylpyridine hydrochloride (2.4 g) and sodium iodide (2.2 g) in acetone (36 cc) is heated under reflux for 2 hours. After cooling to a temperature of about 20° C., the insoluble product formed is filtered off and washed with acetone (3 ⁇ 10 cc) and then with carbon disulphide (3 ⁇ 10 cc).
• Triethylamine (5.25 cc) is added to a suspension of 5-dimethylamino-1,2-dithiol-3-thione (4.45 g), 3-chloromethylpyridine hydrochloride (6.15 g) and sodium iodide (11.25 g) in a mixture of acetone (125 cc) and dimethylformamide (25 cc).
• the reaction mixture is heated under reflux for 6 hours and then filtered whilst boiling.
• the insoluble product formed is collected and washed successively with acetone (40 cc), water (40 cc) and acetone (2 ⁇ 25 cc).
• 5-(Piperidin-1-yl)-1,2-dithiol-3-thione can be prepared by reacting phosphorus pentasulphide (127 g) with ethyl 3-(piperidin-1-yl)-3-oxopropionate (71 g) in pyridine (720 cc) under reflux for 1 hour. The reaction mixture is then cooled to a temperature of about 20° C., diluted with water (6 liters) and extracted with methylene chloride (6 ⁇ 500 cc). The organic phases are combined, washed with distilled water (3 ⁇ 500 cc), dried over magnesium sulphate and filtered, and the filtrate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is taken up in dimethylformamide (90 cc) and the insoluble product is filtered off and washed with dimethylformamide (5 cc) and then with diethyl ether (2 ⁇ 15 cc).
• Ethyl 3-(piperidin-1-yl)-3-oxopropionate can be prepared by reacting piperidine (34 g) with ethyl chloroformylacetate (60 g), in the presence of triethylamine (40.4 g), in methylene chloride (400 cc) at a temperature of about 20° C. for 3 hours.
• 5-(Perhydroazepin-1-yl)-1,2-dithiol-3-thione can be prepared by reacting phosphorus pentasulphide (91.4 g) with ethyl 3-(perhydroazepin-1-yl)-3-oxopropionate (59 g) in pyridine (680 cc) under reflux for 1 hour. The reaction mixture is then cooled to a temperature of about 20° C., diluted with distilled water (6860 cc) and extracted with methylene chloride (780 cc and then 2 ⁇ 560 cc).
• Ethyl 3-(perhydroazepin-1-yl)-3-oxopropionate can be prepared by reacting perhydroazepine (33 g) with ethyl chloroformylacetate (50 g) in the presence of triethylamine (33.6 g), in methylene chloride (333 cc) at a temperature of about 20° C. for 2 hours.
• 5-Morpholino-1,2-dithiol-3-thione can be prepared by reacting phosphorus pentasulphide (53.6 g) with ethyl 3-morpholino-3-oxopropionate (30 g) in pyridine (300 cc) under reflux for 1 hour. The reaction mixture is then cooled to a temperature of about 20° C., hydrolysed with water (3 liters) and extracted with methylene chloride (500 cc). The insoluble product formed is filtered off, washed with diisopropyl ether (2 ⁇ 20 cc) and dried. This gives 5-morpholino-1,2-dithiol-3-thione (3.1 g) melting at 248°-250° C.
• Ethyl 3-morpholino-3-oxopropionate can be prepared by reacting morpholine (17.4 g) with ethyl chloroformylacetate (30.1 g), in the presence of triethylamine (20.2 g), in methylene chloride (200 cc) at a temperature of about 20° C. for 2 hours 30 minutes.
• Chloroacetamide (2.8 g) and sodium iodide (4.95 g) are added to a solution of 5-morpholino-1,2-dithiol-3-thione (4.02 g) in acetone (80 cc), and the reaction mixture is heated under reflux for 3 hours. After cooling to a temperature of about 20° C., the insoluble product formed is filtered off and washed successively with acetone (20 cc), distilled water (3 ⁇ 20 cc) and acetone (40 cc).
• Ethyl 3-phenylamino-3-oxopropionate can be prepared in accordance with the method described by F. D. Chattaway et al., J. Chem. Soc. 97, 939 (1910).
• the corresponding base can be prepared in the following manner:
• Ethyl bromoacetate (4.5 g) is added to a solution of 5-phenylamino-1,2-dithiol-3-thione (4 g) in acetone (70 cc), and the reaction mixture is heated under reflux for 24 hours. After cooling to a temperature of about 20° C., the insoluble product formed is filtered off and washed with acetone (3 ⁇ 5 cc). The filtrates are combined and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C., and the residue is taken up in ethanol (15 cc). The insoluble product is filtered off and washed with ethanol (3 ⁇ 10 cc) and then with diethyl ether (2 ⁇ 10 cc).
• Chloroacetamide (2.15 g) and sodium iodide (3.75 g) are added to a solution of 5-phenylamino-1,2-dithiol-3-thione (3.4 g) in acetone (60 cc).
• the reaction mixture is heated under reflux for 1 hour. After cooling to a temperature of about 20° C., the insoluble product formed is filtered off and washed successively with acetone (20 cc), distilled water (3 ⁇ 20 cc) and acetone (20 cc).
• the corresponding base can be prepared in the following manner:
• the salt obtained as described above is suspended in water (120 cc). Sodium bicarbonate (2.9 g), followed by methylene chloride (250 cc), are then added with stirring. After stirring for 20 minutes, the aqueous phase is decanted and washed with methylene chloride (50 cc). The methylene chloride phases are combined, dried over sodium sulphate and filtered, and the filtrate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C.
• Triethylamine (16.2 g) and then anhydrous pyridine (32 cc) are added dropwise, with stirring and in the course of 15 minutes, to a suspension of 5-phenylamino-1,2-dithiol-3-thione (9 g) and 1-chlorocarbonyl-4-methylpiperazine hydrochloride (23.9 g) in anhydrous methylene chloride (90 cc), kept at a temperature of about 20° C.
• the reaction mixture is then heated under reflux for 3 hours. After cooling to a temperature of about 20° C., the reaction mixture is poured into water (400 cc) and the aqueous phase is decanted and washed with methylene chloride (2 ⁇ 100 cc).
• the methylene chloride phases are combined, dried over sodium sulphate and filtered, and the filtrate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C.
• the residue obtained is dissolved in a methylene chloride/cyclohexane mixture (50/50 by volume; 1.4 liters) and the solution obtained is poured into silica gel (1,400 g) contained in a column of diameter 9 cm. Elution is carried out with a methylene chloride/cyclohexane mixture (50/50 by volume; 7 liters) and then with pure methylene chloride (10 liters). These eluates are discarded.
• Ethyl 3-phenethylamino-3-oxopropionate can be prepared by reacting phenethylamine (42.3 g) with ethyl chloroformylacetate (52.7 g) in anhydrous methylene chloride (425 cc), in the presence of triethylamine (35.4 g), for 2 hours 30 minutes at a temperature of about 20° C. Water (250 cc) is then added to the reaction mixture, and the methylene chloride phase is then decanted and washed successively with a 1 N aqueous solution of hydrochloric acid (250 cc), water (250 cc), a 1 N aqueous solution of sodium hydroxide (250 cc) and water (3 ⁇ 250 cc).
• 5-Ethylamino-1,2-dithiol-3-thione can be obtained by reacting ethyl 3-ethylamino-3-oxopropionate (65 g) with phosphorus pentasulphide (135 g) in pyridine (970 cc) under reflux for 3 hours. After cooling to a temperature of about 20° C., the reaction mixture is hydrolysed with distilled water (6 liters) and then extracted with methylene chloride (1 liter and then 3 ⁇ 500 cc).
• Ethyl 3-ethylamino-3-oxopropionate can be obtained by reacting ethylamine (27 g) with ethyl chloroformylacetate (90.5 g), in the presence of triethylamine (60.5 g), in methylene chloride (600 cc) at a temperature of about 20° C. for 4 hours. After hydrolysis with distilled water (400 cc), the reaction mixture is decanted and the methylene chloride phase is washed successively with distilled water (2 ⁇ 150 cc), with a 1 N aqueous solution of hydrochloric acid (100 cc) and then with distilled water (2 ⁇ 150 cc).
• N,N-Dimethylchloroacetamide (3.7 g) is added to a suspension of 5-(pyrrolidin-1-yl)-1,2-dithiol-3-thione (4.06 g) and sodium iodide (4.9 g) in acetone (70 cc), and the reaction mixture is kept under reflux for 1 hour. After cooling, the insoluble product is filtered off and washed successively with acetone (3 ⁇ 20 cc), with water (3 ⁇ 20 cc) and then with diethyl ether (3 ⁇ 20 cc). The product obtained is then recrystallised once from methanol (150 cc) and then a second time from ethanol (340 cc). This gives N-[5-dimethylcarbamoylmethylthio-1,2-dithiol-3-ylidene]-pyrrolidinium iodide (4.8 g) melting at 152° C.
• 3-Bromoacetylpyridine hydrobromide (6.38 g) is added to a suspension of 5-(pyrrolidin-1-yl)-1,2-dithiol-3-thione (3 g) and sodium iodide (3.3 g) in acetone (54 cc), and the reaction mixture is kept under reflux for 12 hours. After cooling to a temperature of about 20° C., the insoluble product is filtered off and washed successively with acetone (3 ⁇ 20 cc) and then with distilled water (10 cc).
• the corresponding base can be prepared in the following manner:
• the salt obtained as described above is suspended in distilled water (32 cc).
• Sodium bicarbonate (0.84 g) and methylene chloride (50 cc) are then added with stirring. After stirring for 5 minutes, the organic phase is decanted, washed with distilled water (32 cc), dried over magnesium sulphate in the presence of decolorising charcoal, and filtered, and the filtrate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C.
• the corresponding base can be prepared in the following manner:
• the salt obtained as described above is suspended in distilled water (100 cc). Sodium bicarbonate (2.6 g) and methylene chloride (155 cc) are then added with stirring. After stirring for 5 minutes, the organic phase is decanted, washed with distilled water (100 cc), dried over magnesium sulphate in the presence of decolorising charcoal, and filtered, and the filtrate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C.
• Phenacyl chloride (10.5 g) is added to a suspension of 5-morpholino-1,2-dithiol-3-thione (9.85 g) in ethanol (200 cc), and the reaction mixture is kept under reflux for 3 hours. After cooling to a temperature of about 10° C., the insoluble product formed is filtered off and washed with ethanol (30 cc). After drying, N-(5-phenacylthio-1,2-dithiol-3-ylidene)-morpholinium chloride (14.3 g) is obtained, which melts at 138° C. and is solvated by 9% of ethanol.
• the corresponding base can be prepared in the following manner:
• the salt obtained as described above is suspended in distilled water (59 cc).
• Sodium bicarbonate (1.53 g) and methylene chloride (92 cc) are then added with stirring. After stirring for 10 minutes, the organic phase is washed with distilled water (59 cc), dried over magnesium sulphate in the presence of decolorising charcoal, and filtered, and the filtrate is concentrated to dryness under reduced pressure (20 mg Hg; 2.7 kPa) at 40° C.
• the corresponding base can be prepared in the following manner:
• the salt obtained as described above is suspended in distilled water (75 cc).
• Sodium bicarbonate (1.95 g) and methylene chloride (120 cc) are then added with stirring. After stirring for 5 minutes, the organic phase is washed with distilled water (75 cc), dried over magnesium sulphate in the presence of decolorising charcoal, and filtered, and the filtrate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C.
• 2-Bromoacetylthiophene (6.15 g) is added to a suspension of 5-(pyrrolidin-1-yl)-1,2-dithiol-3-thione (4.06 g) and sodium iodide (4.9 g) in acetone (105 cc), and the reaction mixture is kept under reflux for 11/2 hours. After cooling, the insoluble product is filtered off and washed successively with acetone (3 ⁇ 20 cc), with water (3 ⁇ 20 cc) and then with diethyl ether (3 ⁇ 20 cc).
• a suspension of 5-morpholino-1,2-dithiol-3-thione (8 g), ⁇ -bromopropiophenone (11.63 g) and sodium iodide (9 g) in acetone (200 cc) is heated under reflux for 21/2 hours. After cooling to a temperature of about 20° C., the insoluble product is filtered off and washed successively with acetone (3 ⁇ 20 cc), water (5 ⁇ 50 cc) and acetone (3 ⁇ 20 cc).
• ⁇ -Bromo- ⁇ -butyrolactone (4.9 g) is added to a suspension of 5-(pyrrolidin-1-yl)-1,2-dithiol-3-thione (4.06 g) and sodium iodide (4.9 g) in acetone (70 cc), and the reaction mixture is heated under reflux for 6 hours. After cooling, the insoluble product is filtered off and washed successively with acetone (3 ⁇ 20 cc), with water (3 ⁇ 20 cc) and then with diethyl ether (3 ⁇ 20 cc).
• the corresponding base can be prepared in the following manner:
• the salt obtained as described above is suspended in water (50 cc). Sodium bicarbonate (0.6 g) and then methylene chloride (50 cc) are subsequently added with stirring. After stirring for 5 minutes, the aqueous phase is decanted and washed with methylene chloride (20 cc). The methylene chloride phases are combined, washed with distilled water (2 ⁇ 50 cc), dried over magnesium sulphate and filtered, and the filtrate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C.
• Ethyl 3-(3-methoxyphenyl)amino-3-oxopropionate can be prepared by reacting m-anisidine (61.5 g) with ethyl chloroformylacetate (75.3 g), in the presence of triethylamine (50.5 g), in methylene chloride (500 cc) at a temperature of about 15° C. for 16 hours.
• the corresponding base can be prepared in the following manner:
• the salt obtained as described above is suspended in distilled water (45 cc). Sodium bicarbonate (1.1 g) and methylene chloride (70 cc) are then added with stirring. After stirring for 10 minutes, the organic phase is decanted, washed with distilled water (45 cc), dried over magnesium sulphate and filtered, and the filtrate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C.
• Ethyl 3-(4-isopropylphenyl)amino-3-oxopropionate can be prepared by reacting 4-isopropylaniline (109.4 g) with ethyl chloroformylacetate (113 g), in the presence of triethylamine (75.8 g), in methylene chloride (1 liters) at a temperature of about 20° C. for 16 hours.
• 3-Methoxyphenacyl chloride (5.53 g) is added to a suspension of 5-morpholino-1,2-dithiol-3-thione (5.48 g) in ethanol (110 cc), and the reaction mixture is heated under reflux for 6 hours. After cooling to a temperature of about 20° C., the insoluble product is filtered off and washed with ethanol (2 ⁇ 20 cc). By recrystallisation of the resulting product from an ethanol/water mixture (4.4/1 by volume; 135 cc), N-[5-(3-methoxyphenacylthio)-1,2-dithiol-3-ylidene]-morpholinium chloride (5.7 g), melting at 140° C. with decomposition, is obtained.
• 2-Methoxyphenacyl bromide (5.15 g) is added to a suspension of 5-(pyrrolidin-1-yl)-1,2-dithiol-3-thione (3.05 g) and sodium iodide (3.7 g) in acetone (53 cc), and the reaction mixture is kept under reflux for 1 hour. After cooling, the insoluble product is filtered off and washed successively with acetone (3 ⁇ 20 cc), with water (3 ⁇ 20 cc) and then with diethyl ether (3 ⁇ 20 cc).
• 3,4-Dihydroxyphenacyl chloride (7 g) is added to a suspension of 5-(pyrrolidin-1-yl)-1,2-dithiol-3-thione (5.1 g) and sodium iodide (6.2 g) in acetone (90 cc), and the reaction mixture is kept under reflux for 1 hour. After cooling, the insoluble product is filtered off and washed successively with acetone (3 ⁇ 20 cc), with water (3 ⁇ 20 cc) and then with diethyl ether (3 ⁇ 20 cc).
• a suspension of 5-morpholino-1,2-dithiol-3-thione (8 g) and 4-fluorophenacyl chloride (7.54 g) in ethanol (160 cc) is heated under reflux for 6 hours 30 minutes. After cooling to a temperature of about 20° C., the insoluble product formed is filtered off and washed successively with ethanol (3 ⁇ 30 cc) and diethyl ether (50 cc).
• a suspension of 5-morpholino-1,2-dithiol-3-thione (2.7 g) and 4-hydroxyphenacyl chloride (2.52 g) in ethanol (54 cc) is heated under reflux for 8 hours. After cooling to a temperature of about 20° C., the insoluble product is filtered off and washed with ethanol (2 ⁇ 10 cc).
• a suspension of 5-morpholino-1,2-dithiol-3-thione (8 g) and 4-chlorophenacyl chloride (9.2 g) in ethanol (160 cc) is heated under reflux for 10 hours. After cooling to a temperature of about 20° C., the insoluble product is filtered off and washed successively with ethanol (3 ⁇ 30 cc) and diethyl ether (50 cc).
• 2,4-Dichlorophenacyl chloride (9.8 g) is added all at once to a suspension of 5-morpholino-1,2-dithiol-3-thione (8 g) in ethanol (160 cc), and the suspension thus obtained is heated under reflux for 11 hours. After cooling to a temperature of about 20° C., the insoluble product is filtered off and washed successively with ethanol (3 ⁇ 30 cc) and diethyl ether (50 cc).
• a suspension of 5-morpholine-1,2-dithiol-3-thione (8 g) and 4-ainophenacyl chloride (7.41 g) in ethanol (160 cc) is heated under reflux for 7 hours. After cooling to a temperature of about 20° C., the insoluble product is filtered off and washed with ethanol (2 ⁇ 20 cc).
• the product thus obtained is deposited on silica gel (1 kg) contained in a column of diameter 4.5 cm. Elution is carried out successively with a methylene chloride/methanol mixture (99/1 by volume; 1000 cc), a methylene chloride/methanol mixture (98/2 by volume; 500 cc), a methylene chloride/methanol mixture (95/5 by volume; 500 cc) and a methylene chloride/methanol mixture (90/10 by volume; 1000 cc); the corresponding eluates are discarded.
• Elution is then carried out successively with a methylene chloride/methanol mixture (80/20 by volume; 1000 cc), a methylene chloride/methanol mixture (60/40 by volume; 1000 cc), a methylene chloride/methanol mixture (50/50 by volume; 1000 cc) and a methylene chloride/methanol mixture (25/75 by volume; 10000 cc); the corresponding eluates are combined and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C.
• the product thus obtained is suspended in methylene chloride (100 cc) and, after stirring for 15 minutes, the insoluble material is filtered off. After drying, N-[5-(4-aminophenacylthio)-1,2-dithiol-3-ylidene]-morpholinium chloride (7 g), melting at 220° C., is obtained.
• a suspension of 5-morpholino-1,2-dithiol-3-thione (8 g) and 4-cyanophenacyl chloride (8.7 g) in ethanol (160 cc) is heated under reflux for 6 hours. After cooling to a temperature of about 20° C., the insoluble product is filtered off and washed successively with ethanol (3 ⁇ 30 cc), carbon disulphide (30 cc) and diethyl ether (30 cc).
• a suspension of 5-morpholino-1,2-dithiol-3-thione (8 g) and 3-chlorophenacyl chloride (8.8 g) in ethanol (160 cc) is heated under reflux for 6 hours. After cooling to a temperature of about 20° C., the insoluble product is filtered off and washed successively with ethanol (3 ⁇ 30 cc) and diethyl ether (50 cc).
• a suspension of 5-morpholino-1,2-dithiol-3-thione (5 g), 2-chlorophenacyl chloride (7.6 g) and sodium iodide (5.6 g) in acetone (115 cc) is heated under reflux for 30 minutes. After cooling to a temperature of about 20° C., the insoluble product is filtered off and washed successively with acetone (20 cc), water (20 cc) and diethyl ether (20 cc).
• Methyl iodide (3.4 g) is added to a solution of 5-dimethylcarbamoylthio-3-phenylimino-1,2-dithiole (2.37 g), prepared as described in Example 32, in acetone (50 cc) under reflux, and reflux is maintained for 3 hours. After cooling to a temperature of about 20° C., the insoluble product formed is filtered and washed with acetone (10 cc).
• a suspension of 5-morpholino-1,2-dithiol-3-thione (2.62 g), 4-methoxyphenacyl bromide (4.12 g) and sodium iodide (3 g) in acetone (60 cc) is heated to the reflux temperature and maintained there for 2 hours. After cooling to a temperature of about 20° C., the insoluble product is filtered off and washed successively with acetone (30 cc), distilled water (2 ⁇ 40 cc) and acetone (2 ⁇ 30 cc). The product thus obtained is suspended in methylene chloride (110 cc). After stirring for 1 hour at a temperature of about 20° C., the insoluble product is separated by filtration. N-[5-(4-Methoxyphenacylthio)-1,2-dithiol-3-ylidene]-morpholinium iodide, melting at 152°-155° C., is thus obtained.
• the present invention also relates to the pharmaceutical compositions which comprise a compound of general formula (I) in the form of a pharmaceutically acceptable salt or, if appropriate, in the free base form, in accordance with any other pharmaceutically compatible product, which can be inert or physiologically active.
• the compositions according to the invention can be administered orally, parenterally or rectally.
• compositions for oral administration can be used as solid compositions for oral administration.
• the active product according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica.
• these compositions can also comprise substances other than diluents, e.g. one or more lubricants, such as magnesium stearate or talc, a colorant, a coating (coated tablets) or a lacquer.
• Liquid compositions for oral administration include pharmaceutically-acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents, such as water, ethanol, glycerol, vegetable oils or paraffin oil. Besides inert diluents such compositions may also comprise adjuvants such as wetting, sweetening, thickening, flavouring or stabilising agents.
• Preparations according to the invention for parenteral administration include sterile aqueous or nonaqueous solutions, suspensions or emulsions.
• Water, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, e.g. ethyl oleate, or other suitable organic solvents can be employed as the solvent or vehicle.
• These compositions may also contain adjuvants, in particular wetting agents, isotonic agents, emulsifiers, dispersing agents and stabilisers.
• Sterilisation can be carried out in several ways, e.g., by filtration under aseptic conditions, by incorporating sterilising agents into the composition, by irradiation or by heating.
• the compositions can also be prepared in the form of sterile solid compositions which can be dissolved in an injectable sterile medium immediately before use.
• compositions for rectal administration are suppositories or rectal capsules, which, in addition to the active product, contain excipients, such as cacao butter, semi-synthetic glycerides or polyethylene glycols.
• the compounds according to the invention are particularly useful as cytoprotective agents in the treatment of ulcers of the digestive system.
• the doses depend on the desired effect and on the duration of the treatment; adult doses are generally between 7 and 700 mg per day, administered orally in one or more portions.
• the physician will determine the dosage considered most appropriate, taking into account the age, the weight and all of the other factors intrinsic to the patient being treated.
• Tablets containing 50 mg doses of active product and having the following composition are prepared in accordance with the usual technique:
• Tablets containing 50 mg doses of active product and having the following composition are prepared in accordance with the usual technique:

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• 1982
  • 1982-06-17 FR FR8210616A patent/FR2528843A2/fr active Pending
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  • 1982-08-06 EP EP82401502A patent/EP0072743A1/fr not_active Withdrawn
  • 1982-08-10 GR GR69004A patent/GR76889B/el unknown
  • 1982-08-10 DK DK359382A patent/DK359382A/da not_active Application Discontinuation
  • 1982-08-10 US US06/406,980 patent/US4407797A/en not_active Expired - Fee Related
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  • 1982-08-11 FI FI822802A patent/FI822802A7/fi not_active Application Discontinuation
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